Research

CR6086: Prostaglandin EP4 receptor antagonist

Rheumatoid Arthritis immunomodulation

CR6086 is a novel small molecule acting as a potent and selective antagonist of the prostaglandin E2 receptor EP4 subtype (EP4 receptor).

Recent studies have shown that prostaglandin E2, via the EP4 receptor, plays a key role as a cytokine amplifier, in T-cell differentiation and expansion, and thus in the altered immune response observed in autoimmune diseases such as rheumatoid arthritis. These findings point to the EP4 receptor as a rational target for novel disease-modifying antirheumatic drugs (DMARDs)/immunomodulators which, in addition, have direct anti-inflammatory properties distinct from the general effects of NSAIDs.

In animal models of rheumatoid arthritis, CR6086 performs better than first-line immunomodulatory agents such as methotrexate, better than nonsteroidal anti-inflammatory drugs (NSAIDs), and similarly to DMARDs for the advanced disease (e.g. the immunosuppressant JAK inhibitor tofacitinib) or even biologicals (e.g. the TNF inhibitor etanercept).

The three completed Phase I studies of this compound have shown a very good safety/tolerability profile and favourable pharmacokinetics, with relevant concentrations for target engagement.

Rheumatoid arthritis is the first indication where the therapeutic potential of CR6086 will be explored. The plan is to develop CR6086 as a first-line therapy in early RA, with the objective to provide the early disease modification that may delay both the progression of the disease and the recourse to biological or targeted synthetic DMARDs. Still, nonclinical models indicate high efficacy even in more advanced stages of rheumatoid arthritis.

A first Phase II, randomized, double blind, placebo-controlled, dose response trial of 12 weeks duration in DMARD-naïve, early RA patients in combination with methotrexate is ongoing.